The sympathetic nervous system is an important modulator of cardiovascular function that contributes to the development and maintenance of cardiovascular disease. The effects of the sympathetic nervous system are mediated via the release of neurotransmitters and neuropeptides from nerve terminals innervating blood vessels and the heart. The mechanisms underlying the development and/or maintenance of cardiovascular sympathetic innervation are not understood. The experiments described in this proposal will consider how vascular cells affect vascular sympathetic innervation. In aim 1 we will test the hypothesis that vascular cells from innervated blood vessels (femoral and tail arteries) promote sympathetic innervation by promoting axon growth, guidance, target recognition and/or synapse formation. In aim 1 we will also test the hypotheses that vascular-induced increases in cGMP, and vascular-derived VEGF, ephrins and integrin ligands mediate the effects of innervated vascular cells. In aim 2 we will test the hypothesis that vascular cells from non-innervated blood vessels (aortas and carotid arteries) inhibit sympathetic innervation by inhibiting axon growth, guidance, target recognition, and/or synapse formation. In aim 2 we will also test the hypotheses that vascular-derived leukemia inhibitory factor (LIF), and semaphorin 3A mediate the effects of non-innervated vascular cells. The effects of vascular cells will be studied in vitro using cell and organ cultures. The mechanisms underlying vascular effects will be studied in vitro and in vivo. The role of LIF will also be studied using a transgenic mouse model (LIF -/-). The results of the proposed studies will indicate if and how vascular cells promote or inhibit vascular sympathetic innervation, will provide novel insight into the mechanisms underlying innervation, and may suggest novel approaches for promoting reinnervation following denervation or for decreasing innervation in pathologies associated with excess innervation or activity.